Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

Koo, Ja Wook; Lobo, Mary Kay; Chaudhury, Dipesh; Labonté, Benoit; Friedman, Allyson K.; Heller, Elizabeth A.; Peña, Catherine J.; Han, Ming; Nestler, Eric J.

doi:10.1038/npp.2014.118

Cited by 102 publications

(85 citation statements)

References 38 publications

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“…We also noted that several glutamate receptor subunits (Gria4, Grin2d, Grin3a) were upregulated by interrupted morphine, but only in comparison to control in the nucleus accumbens. These changes are consistent with plasticity of excitatory and inhibitory synaptic transmission caused by intermittent morphine exposure (50)(51)(52).…”

Section: Genes and Pathways Regulated By Interrupted Morphine Exposuresupporting

confidence: 81%

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

Lefevre

Pisansky

Toddes

et al. 2019

Preprint

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Background: Drug-evoked adaptations in the mesolimbic dopamine system drive opioid abuse and addiction, but these adaptations vary in magnitude and direction following different patterns of opioid exposure. Despite fundamental links between the pattern of drug exposure and abuse liability, few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. Methods:In male and female mice, we first compared the behavioral consequences of chronic morphine exposure for one week, across multiple doses and with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with twice-daily naloxone injections, and used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum.Results: Continuous morphine exposure caused tolerance to both the antinociceptive and psychomotoractivating effects of morphine. In contrast, both intermittent and interrupted morphine exposure caused longlasting psychomotor sensitization. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in the nucleus accumbens and dorsal striatum, dramatically increasing the number of differentially expressed transcripts and engaging unique signaling pathways. Conclusions:These experiments indicate that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may therefore represent a strategy to minimize detrimental effects on brain reward circuits. This may in turn reduce the risk of progression from opioid use to abuse, promoting safer use of opioid-based treatments for clinical indications.

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Section: Genes and Pathways Regulated By Interrupted Morphine Exposuresupporting

confidence: 81%

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

Lefevre

Pisansky

Toddes

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Koo et al (2014) have also observed a negative relationship between accumbens BDNF and morphine CPP memory, but in a cell-type specific manner. That is, selective ablation of the TrkB BDNF receptor on dopamine D1 receptor-containing medium spiny neurons resulted in reduced GABA-A receptor currents in these neurons, ultimately promoting morphine reward (Koo et al, 2014). Given that morphine exposure led to a similar cell-type specific downregulation of TrkB in D1-neurons, the authors hypothesized that this neuroadaptation contributes to morphine addiction.…”

Section: Bdnf and Opiate Seekingmentioning

confidence: 82%

Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

et al. 2015

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Many abused drugs lead to changes in endogenous brain-derived neurotrophic factor (BDNF) expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural circuits are responsible for storing and executing drug-procuring motor programs, whereas other neural circuits are responsible for the active suppression of these “seeking” systems. These seeking-circuits are established as associations are formed between drug-associated cues and the conditioned responses they elicit. Such conditioned responses (e.g. drug seeking) can be diminished either through a passive weakening of seeking-circuits or an active suppression of those circuits through extinction. Extinction learning occurs when the association between cues and drug are violated, for example, by cue exposure without the drug present. Cue exposure therapy has been proposed as a therapeutic avenue for the treatment of addictions. Here we explore the role of BDNF in extinction circuits, compared to seeking-circuits that “incubate” over prolonged withdrawal periods. We begin by discussing the role of BDNF in extinction memory for fear and cocaine-seeking behaviors, where extinction circuits overlap in infralimbic prefrontal cortex (PFC). We highlight the ability of estrogen to promote BDNF-like effects in hippocampal–prefrontal circuits and consider the role of sex differences in extinction and incubation of drug-seeking behaviors. Finally, we examine how opiates and alcohol “break the mold” in terms of BDNF function in extinction circuits.

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“…Similarly, optical activation of NAc D1-, but not D2-MSNs enhances morphine CPP (Koo et al, 2014). Indeed, recent evidence reveals expression of μ-opioid receptors within NAc D1-MSNs of the direct pathway to be necessary to support opiate-induced CPP and locomotor sensitization (Cui et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Striatal direct and indirect pathways control decision-making behavior

2014

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Despite our ever-changing environment, animals are remarkably adept at selecting courses of action that are predictive of optimal outcomes. While requiring the contribution of a number of brain regions, a vast body of evidence implicates striatal mechanisms of associative learning and action selection to be critical to this ability. While numerous models of striatal-based decision-making have been developed, it is only recently that we have begun to understand the precise contributions of specific subpopulations of striatal neurons. Studies utilizing contemporary cell-type-specific technologies indicate that striatal output pathways play distinct roles in controlling goal-directed and social behaviors. Here we review current models of striatal-based decision-making, discuss recent developments in defining the functional roles of striatal output pathways, and assess how striatal dysfunction may contribute to the etiology of various neuropathologies.

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Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

Cited by 102 publications

References 38 publications

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

Striatal direct and indirect pathways control decision-making behavior

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